Abstract 2454: Cardiac Sodium Channel Mutations are Prevalent in a Cohort of Mexican-Mestizo Patients with Malignant Long QT Syndrome
Background: Ten long QT syndrome (LQTS) susceptibility genes have been identified to date. Among Caucasians and Europeans, the yield of LQTS genetic testing is about 75% with mutations in SCN5A (LQT3) causing 5–10% of all known LQTS. The spectrum and prevalence of LQTS-associated mutations among other ethnicities is poorly understood.
Methods: Between June 2004 and April 2005, 12 Mexican-Mestizo probands (8 males, mean age 16 ± 15 years, mean QTc = 566 ms) with phenotypically severe LQTS were referred for genetic screening. After obtained written informed consent from all participants, comprehensive open reading frame/splice site mutational analysis of KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6) was performed using denaturing high performance liquid chromatography and direct DNA sequencing. Negative cases were subjected to further mutational analysis of ANKB (LQT4), KCNJ2 (LQT7), CACNA1C (LQT8), CAV3 (LQT9), and SCN4B (LQT10). All non-synonymous variations were screened for in 200 ethnicity-matched reference alleles (Mexican-Mestizo ethnicity results from the admixture between Native American and European, with a smaller contribution of African groups) and 2600 additional reference alleles derived from healthy whites, blacks, and Asians
Results: We identified 8 non-synonymous variants and 2 frame shift deletions in 9/12 (75%) probands including JLN1 (2), LQT3 (5), LQT4 (1), and LQT10 (1). The mutations involve conserved residues and localize to key structure-function domains. Except for R1450W-ANKB which was also seen in 1 healthy black control, 7 are novel (58%). None of the mutations were seen in the 2800 reference alleles. In contrast to the 5–10% prevalence for SCN5A-mediated LQT3 among Caucasian/European LQTS, perturbations in the sodium channel macromolecular complex was the predominate pathogenic substrate among this Mexican Mestizo cohort with malignant LQTS.